The search for, and chemistry and mechanism of, neurotrophic natural products.

Neurotrophic factors, now termed neurotrophins, which belong to a class of polypeptidyl agents, have been shown to potentially be beneficial for the treatment of neurodegenerative diseases such as Alzheimer's disease, because endogenous neurotrophic factors (NGF, BDNF, NT3, NT4) have been recognized to play critical roles in the promotion of neurogenesis, differentiation, and neuroprotection throughout the development of the central nervous system. However, high-molecular weight proteins are unable to cross the blood-brain barrier and are easily decomposed by peptidase under physiological conditions. To address this issue, small molecules that can mimic the functions of neurotrophic factors would be promising alternatives for the treatment of neurodegenerative disease. We have continued to search for natural products having typical neurotrophic properties, which can cause neurogenesis, enhance neurite outgrowth, and protect neuronal death using three cellular systems (PC12, rat cortical neurons, and MEB5 cells). In this review, we summarize the neurotrophic activities and synthesis of dimeric isocuparane-type sesquiterpenes from the liverwort, Mastigophora diclados, the mechanism of neurotrophic neolignans, magnolol, honokiol and their sesquiterpene derivatives, and introduce unique neurotrophin-mimic natural products, including seco-prezizaane-type sesquiterpenes from the Illicium species, vibsane-type diterpenes from Viburnum awabuki, and miscellaneous natural products with neurotrophic effects discovered by us.